Valproic Acid Stimulates Proliferation and Self-renewal of Hematopoietic Stem Cells

Abstract

Histone deacetylase inhibitors have attracted considerable attention because of their ability to overcome the differentiation block in leukemic blasts, an effect achieved either alone or in combination with differentiating agents, such as all-trans retinoic acid. We have previously reported favorable effects of the potent histone deacetylase inhibitor valproic acid in combination with all-trans retinoic acid in patients with advanced acute myeloid leukemia leading to blast cell reduction and improvement of hemoglobin. These effects were accompanied by hypergranulocytosis most likely due to an enhancement of nonleukemic myelopoiesis and the suppression of malignant hematopoiesis rather than enforced differentiation of the leukemic cells. These data prompted us to investigate the effect of valproic acid on normal hematopoietic stem cells (HSC). Here we show that valproic acid increases both proliferation and self-renewal of HSC. It accelerates cell cycle progression of HSC accompanied by a down-regulation of p21 cip-1/waf-1 . Furthermore, valproic acid inhibits GSK3B by phosphorylation on Ser9 accompanied by an activation of the Wnt signaling pathway as well as by an up-regulation of HoxB4, a target gene of Wnt signaling. Both are known to directly stimulate the proliferation of HSC and to expand the HSC pool. In summary, we here show that valproic acid, known to induce differentiation or apoptosis in leukemic blasts, stimulates the proliferation of normal HSC, an effect with a potential effect on its future role in the treatment of acute myeloid leukemia. (Cancer Res 2005; 65(7): 2537-41)

Epigenetic regulation of aging stem cells

“…Differences in the functional phenotypes caused by the deficiencies of different HDACs emphasize the need for a more complete understanding of HDAC specificity in adult NSCs. Contrary to what is observed in NSCs, inhibition of HDAC activity by the addition of valproic acid increases proliferation of HSCs without affecting differentiation (Bug et al, 2005), suggesting that the regulation and importance of histone acetylation is specific to stem cell types.…”

The ups and downs of Wnt signaling in prevalent neurological disorders

“…Subsequently, morphological abnormalities similar to those found in autistic individuals have been reported in animals exposed to valproic acid prenatally (Rodier et al, 1997;Ingram et al, 2000;Miyazaki et al, 2005). Interestingly, valproic acid has been shown to activate Wnt-dependent gene expression by a complex mechanism involving inhibition of GSK3b and histone deacetylase (HDAC) activities (Chen et al, 1999;Phiel et al, 2001;Hall et al, 2002;Bug et al, 2005). Therefore, valproic acid can activate Wnt signaling and thus Wnt signaling may in part explain the teratogenic effect of the drug.…”

The t(6;9) associated DEK/CAN fusion protein targets a population of long-term repopulating hematopoietic stem cells for leukemogenic transformation

“…The competitive re-population assay was based on the CD45.1FCD45.2 chimerism of C57BL/6N mice as previously described. 22 Immediately after retroviral infection, 1 Â 10 4 CD45.1 þ /Sca1 þ /lin À cells were injected into lethally irradiated (11 Gy) CD45.2 þ female recipients together with 5 Â 10 5 normal Ly5.2 þ BM cells. The proportion of CD45.1 þ donor cell-derived hematopoietic cells was determined by flow cytometry of peripheral blood or BM mononuclear cells.…”